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Childhood cancer in India
Cancer Epidemiology xxx (xxxx) xxxx
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Childhood cancer in India Shuvadeep Gangulya, Sally Kinseyb, Sameer Bakhshia,* a b
Department of Medical Oncology, IRCH, AIIMS, New Delhi, India Department of Paediatric Haematology, University of Leeds, Honorary Consultant Paediatric Haematologist, Leeds Teaching Hospitals Trust, Leeds, UK
ARTICLE INFO
ABSTRACT
Keywords: Child Cancer India Survival Incidence Epidemiology Mortality Health services
India has made significant improvement in childhood cancer services in last few decades. However, the outcome still remains modest as compared to global standards due to significant barriers in recognition, diagnosis and cure. Data regarding comprehensive childhood cancer burden in country is lacking due to low and urban predominant coverage of population-based cancer registry programs. The available data shows lower incidence of childhood cancer incidence especially in leukaemia and CNS tumours which may suggest poor awareness of caregivers and delayed diagnosis with many “missed cases”. Incidence data are also skewed towards male preponderance which suggests gender bias in seeking healthcare. The childhood cancer services in India are predominantly restricted to few tertiary care centres in major cities. The outcome in major groups of cancer is complicated by delayed and more advanced stage of presentation and poor supportive care during intensive treatment. Treatment refusal and abandonment remains major hurdles. Last few decades saw development of dedicated paediatric oncology services and training programs in the country. The development of InPOG (Indian Paediatric Oncology group) for conducting collaborative trials will lead to adoption of uniform treatment protocols suited for the country. Financial support through the government promoted health insurance and holistic support through philanthropic organizations have improved treatment adherence and outcome. Moving forward, the focus should be on strengthening the cancer registries for capturing nationwide data, improving awareness of childhood cancer among caregivers and healthcare workers for early recognition and improving accessibility of childhood cancer care services beyond major cities.
1. Background Currently, more than 80 % of children diagnosed with cancer will become long-term survivors in high income countries (HICs) [1]. Low and middle-income countries (LMICs), including India, account for nearly 90 % of paediatric population and more than 80 % of childhood cancer burden [2,3]. Inequality in healthcare access, lack of adequately trained manpower, treatment abandonment and myriad of other factors have led to only modest improvement in childhood cancer outcome in LMICs in contrast to HICs [4]. In India, although great progress has been made in last few decades, a lot of barriers exist in the pathway from diagnosis to cure. There is lack of high-quality data which captures nation-wide incidence, survival and morbidity of childhood cancer [5]. The focus of healthcare policy of the country is towards more pressing issues like reproductive
health, communicable diseases, malnutrition with less focus towards childhood cancer which forms significantly small proportion of total cancer cases. In this review, we compare incidence and outcome of childhood cancer in India with global standards, attempt to elucidate various barriers in pathway from diagnosis to cure in different healthcare settings of the country, summarize the progress made so far and the way forward. 2. Childhood cancer burden in India: comparison with global standards The data on childhood cancer burden in India predominantly stems from population-based cancer registries (PBCRs) and hospital-based cancer registries (HBCRs) along with disease-specific institutional
⁎ Corresponding author at: Department of Medical Oncology Dr. BRA Institute Rotary Cancer Hospital All India Institute of Medical Sciences, New Delhi, 110029, India. E-mail address: [email protected] (S. Bakhshi).
https://doi.org/10.1016/j.canep.2020.101679 Received 18 October 2019; Received in revised form 8 January 2020; Accepted 9 January 2020 1877-7821/ © 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Shuvadeep Ganguly, Sally Kinsey and Sameer Bakhshi, Cancer Epidemiology, https://doi.org/10.1016/j.canep.2020.101679
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Fig. 1. Location of population-based cancer registries and hospital based cancer registries in India (*Map of India adapted from outline map of India from Survey of India, Department of Science and Technology, Govt of India).
of Million Death study estimated childhood cancer mortality at 37/ million/year; this is significantly higher than previous estimates with large disparity noted in CNS tumours; notably, only around 4–5 % of children received any form of cancer-directed therapy before death, even though 82.5 % presented to hospital facilities before death. This highlights significant barriers that exist in accessing cancer healthcare services for children [11].
reviews. Currently, with 33 PBCRs and 29 HBCRs functioning in India including regional cancer centres (Fig. 1) and with new centres being constantly added to the network, population coverage still remains low at only 10 % with significant urban dominance [5,6]. Cancer incidence patterns are related with socio-economic development with HICs reporting higher incidence compared to LMICs [4,7]. Childhood cancer in India accounts for 0.7-4.4 % of total cancer diagnoses as per PBCR report (2012-14) which is nearly similar to previous PBCR report of 0.5-5.8 % (2009-11) [8,9]. Age-adjusted incidence rate per million (AARpm) showed a wide variation with Delhi having highest AARpm for all types of childhood cancers in both boys and girls at 235.3and 152.3 respectively followed by PBCR Chennai in South India (156.7 for boys and 85.6 for girls) and Aizawl district in north-eastern India (136.1 for boys and 88.7 for girls) [8]. This unusual high incidence of childhood cancer in Delhi is likely due to referral bias in view of the location of major hospitals with paediatric oncology services in the capital although, the role of exposure to other risk factors needs to be investigated. As per the report of International Incidence of childhood cancer volume-3, age-standardized rate of childhood cancer incidence in India from records of 7 registries is 96.9 pm which is significantly lower than countries like US (166.9 pm), Canada (164.9 pm), UK (140.5 pm) or Australia (154.9 pm) (Fig. 2A and B) [7]. It is worthwhile to note the gender variation in childhood cancer incidence in India where male to female ratio is 1.56 while it is between 1.12–1.15 in HICs, which may suggest gender bias in seeking care (Fig. 3). Gender-based discrimination against girl child is a phenomenon seen in Southeast Asian countries which translates into delayed healthcare seeking for all childhood illnesses including cancer [10]. The incidence of central nervous system (CNS) tumours and leukaemia is significantly lower than in HICs (Fig. 2A and B), which perhaps signify that a large proportion of cases remain undiagnosed. A nationally representative study which used verbal autopsy reports
3. Pathway to cure and its barriers The epidemiology and outcome of respective childhood cancers in Indian context is summarized along with discussion about existing gaps and limitations specific to each group along with suggestions to improve the existing barriers (Tables 1 and 2) 3.1. Leukaemia Leukaemia accounts for 40–50 % of childhood cancer burden in India with acute lymphoblastic leukaemia (ALL) being the commonest type [7,12]. There is a paucity of population-based studies showing outcome of paediatric ALL in India, however, one study showed 5-year overall survival (OS) of 38.7 % (1990–2001) [13]. A recent review summarizing the outcome of ALL in various hospital-based studies, showed OS between 45–81 % and event free survival (EFS) between 41–70 % although, outcome in patients who defaulted was unknown [14–19]. The median age of presentation in various studies is between 6–10 years which is comparatively later than in HICs [14,20]. The initial multi-centric study, which attempted to elucidate risk factors for paediatric ALL in India, showed increased WBC count and more extensive disease (in form of lymphadenopathy and hepatosplenomegaly) at presentation, more frequency of T-cell immunophenotype (21.1–42.7 %) with lower percentage of TEL-AML1 and higher percentage of BCR2
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Fig. 2. A: Age standardized incidence rates of major groups of childhood cancer (0–14years) in India and comparison with selected population (Data compiled from International Incidence of Childhood cancer volume III [7]). B: Relative proportion of major group of childhood cancer in India and other selected countries (Data compiled from International Incidence of Childhood cancer volume III [7]).
ABL positive cases [17,21]. Similar findings have been reported in other studies though, it is prudent to observe that cytogenetic and molecular analysis could not be routinely done in most centres due to paucity of resource, availability and expertise [16,19,22]. This late median age of presentation and high-risk disease phenotype may suggest a high-risk disease biology in Indian ethnicity. However, it may also be due to the fact that more florid presentation with high risk disease biology may be easily recognized and referred while more insidious onset TEL-AML1 transcript positive pre-B ALL cases are likely missed or recognized significantly late. A study from North India showed initial treatment refusal rate of 30.2 % and subsequent rate of treatment default of around 14.5 % [18]. Treatment default significantly occurred during induction and is multifactorial [23,24]. In paediatric AML, a recent review reported 6–45 % toxicity-related deaths in various studies and relapse rates between 26–48 % [14]. Five-
year OS from an institutional series from North India was 35.5 % with induction mortality of 18 % [25]. A significant proportion of patients have extramedullary presentation which is associated with better outcome [26]. The treatment refusal rate ranged from 6 to 20% in tertiary care centres in India and financial support necessary for majority of families for affording care in first tier cities was possible only in major government-funded hospitals [27]. 3.2. Lymphoma The overall incidence of childhood lymphoma in India is similar to that of Western population; the relative proportion of Hodgkin lymphoma (HL) was higher in earlier epidemiological review although this finding was not reflected in latest PBCR report [7,8,12].
Fig. 3. Age standardized incidence rate per million of childhood cancer of boys and girls in India and other selected countries (Data compiled from International Incidence of Childhood cancer volume III [7]). 3
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Table 1 General barriers in the pathway to childhood cancer diagnosis and cure in India with suggestions for improvement. Barriers 1 Barriers to diagnosis a Late presentation to the healthcare facility
a Delayed diagnosis
Probable underlying factors
Suggestions for addressing the barrier
of awareness among caregivers regarding early signs (like • Lack leukocoria in retinoblastoma) for traditional or alternative medications • Preference of healthcare facilities nearby • Inaccessibility and socio-economic status • Education • Gender bias in seeking healthcare for girl child of expertise in grassroots healthcare workers in recognizing • Lack signs of childhood cancer (missed cases of CNS tumours, misdiagnosis of tuberculosis)
of diagnostic facilities in peripheral centres with lack of • Lack expertise for interpretation (especially MRI facilities, 2 Barriers to cure a Treatment denial and abandonment [79]
a Treatment toxicity a Suboptimal care
immunophenotyping)
belief and irrational fear about cancer curability • Personal difficulties and logistics • Financial with care received • Dissatisfaction for key interventions which are aggressive (enucleation/ • Refusal amputation) or have multiple painful procedures (bone marrow/ intrathecal drug administration)
support structure, lack of transfusion support • Poor • Malnutrition incidence of sepsis • High is localized in few centres • Expertise of co-ordination between specialists for constitution of • Lack tumour boards. availability of anti-neoplastic drugs [80] • Less surgery or treatment at peripheral healthcare centre • Suboptimal (especially Wilms tumour and neuroblastoma) or by alternative
of parents and general population about common • Education childhood cancers and its high curability. of healthcare delivery facilities at peripheral level • Improvement through community wellness centres as envisioned under Ayushman Bharat program.
of population towards gender bias through • Sensitization government flagship programs. of healthcare workers and general practitioners/ • Training paediatricians for recognising early signs of childhood cancer. of paediatric oncology services through district level • Strengthening healthcare facilities.
counselling to allay anxiety of caregivers and to • Pre-treatment inform about high curability of childhood cancers and need for complete treatment to achieve good outcome.
tracking mechanisms and telephonic follow up for • Effective minimizing dropouts of holistic support structure for transfusion • Development support, nutrition through collaborations, accommodation
support for financially needy patients from faraway places.
programs for paediatric oncology as well as allied • Training services to disseminate expertise. decision making through multi-disciplinary tumour • Increasing boards to ensure proper and complete treatment delivery
medicine practitioners
*CNS = Central Nervous System, MRI = Magnetic resonance imaging.
3.2.1. Hodgkin lymphoma HL in India is characterized by younger age of presentation and predominance of mixed cellularity histopathology which may be due to subclinical Epstein Barr Virus infection in childhood [12,28]. In various institutional reviews, between 40–60 % of children presented with advanced stage disease with more proportion of patients reporting B symptoms [28,29]. Indolent nature of presentation and frequent misdiagnosis of tuberculosis, especially in a high tuberculosis prevalence area like India, contributes to delayed presentation and similar findings have been observed in other settings as well [30]. In an institutional series, 46 % of patients received empirical anti-tubercular therapy before diagnosing HL which suggests need for generating awareness for early suspicion and referral [28]. Five-year OS in paediatric HL is above 90 % with EFS between 83–87 % which is almost similar albeit slightly lower than HICs [1,28,29]. In early stage HL, the survival outcome is excellent with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) regimen with 10-year OS of 98.9 % [31]. Even in advanced cases, ABVD has reasonable outcome with 5-year OS of 95.3 % and freedom from treatment failure of 84.8 % [32]. This encouraging finding suggests that survival outcome of paediatric HL in India nearly parallels global standards which may be likely due to simpler treatment protocols and intrinsic chemosensitivity of the disease, although delayed presentation remains a major barrier.
EFS of 72 %, 55.8 % and 27.5 % in BL, ALCL and DLBCL respectively, while outcome with uniform BFM-90 protocol in advanced paediatric BNHL from North India showed 5-year OS of 61 % and EFS of 52 %, which is inferior to HICs [34,36]. In early-stage non-blastic NHL, short course reduced intensity protocol achieved reasonably good outcome with possible reduced toxicities [37]. The data regarding accessibility of multi-disciplinary care, treatment abandonment or denial in paediatric NHL is lacking which precludes extrapolation of these findings on overall Indian population. 3.3. CNS tumours CNS tumours account for 8–12 % of total childhood cancer cases as per consolidated HBCR (2012-14) report [38]. In a multi-institutional review, astrocytoma and medulloblastoma remains the two most common paediatric brain malignancy followed by primitive neuro-ectodermal tumour, craniopharyngioma and ependymal tumours [39]. The relative proportion of tumours is similar to Western data with a relatively higher incidence of craniopharyngioma in India [39–41]. The relatively lower incidence of paediatric CNS tumours in India may be likely due to poor recognition and missed diagnosis as the common presenting symptoms are headache, vomiting and seizures, which can often be non-specific in younger children [42]. Hence, in absence of readily available neuro-imaging and neurosurgical facilities which is limited to predominantly tertiary care institutions, a large proportion of cases may be misdiagnosed and treated as meningo-encephalitis [12]. A retrospective institutional review showed 15.3 % mortality on follow-up however, another 44 % abandoned treatment and subsequent outcome was not reported; only 56 % could receive complete treatment as per protocol [43]. Another study also reported 32 % refusal rate for radiotherapy after surgery.(14) The above findings suggest that multimodality treatment even though available in select centres could not be
3.2.2. Non-Hodgkin lymphoma (NHL) In institutional reviews, the most common presenting feature is abdominal symptoms followed by constitutional symptoms and lymphadenopathy with a significant proportion of cases presenting in advanced stages [33–35]. Burkitt’s lymphoma (BL) (40–60 %) and lymphoblastic lymphoma (30–40 %) remains the predominant subtypes followed by anaplastic large cell lymphoma (ALCL) and diffuse large Bcell lymphoma (DLBCL). Experience from South India showed 2-year 4
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Table 2 Differences in presentation and outcome of specific groups of childhood cancer in India with disease specific barriers to management: Group of childhood cancer Leukaemia ALL
•
• AML
Lymphoma Hodgkin lymphoma(HL)
•
• Non Hodgkin lymphoma CNS Tumours
Retinoblastoma
Other solid tumours Neuroblastoma Wilms’ tumour Bone tumours Osteosarcoma Ewing’s sarcoma Rhabdomyosarcoma
• • •
Presentation in India as compared to HICs
Outcome in India as compared to HICs
Specific barriers in management
age of presentation (6–10 years) 45–81 % compared to nearly 90% recognition of insidious onset pre-B ALL • Later • OS • Delayed [14,20] in HICs. [14,57] (anaemia and fever are often missed or treated for nutritional anaemia) T-cell immunophenotype • More high-risk cytogenetics/molecular Lack of easy availability of immunophenotyping • More • features [17,21] and expertise in peripheral centres leading to delayed diagnosis and repeated bone marrow proportion with Data is scarce with 5-year OS of 30–35 • Significant • extramedullary presentation (up to % (compared to 68% in HICs) examinations. 21.2 %) [26] [25,26,57] abandonment especially in induction • Treatment phase with multiple painful procedures (Intrathecal
age of presentation (8-10years) OS around 90 % (compared to • Earlier • 5-98 year • [28] % in HICs) [28,29,57] proportion of mixed cellularity • More histopathology [28] • children with advanced stage stage and 90 • More • 5%yrinOSearly61 %stagein advanced /with B symptoms [34,35] (compared to more than 80 % in HICs) [36,37,57]
drug administration/ bone marrow) or due to toxicity (experienced in up to 45 % of patients during AML induction [14]) Delayed recognition due to misdiagnosis of tuberculosis (seen in up to 46 % of diagnosed cases of HL). [30] Common use of steroids in peripheral healthcare facility without diagnosis complicates the diagnosis of leukaemia or lymphoma further down the line.
of CNS tumours is nearly 50 data. 15.3 % mortality in recognition or missed diagnosis due to • Incidence • Scarce • Delayed % of that in HICs. [7] institutional follow up (with significant non-specific symptoms in younger children and treatment drop out) [43] lack of easily available neuro-imaging and neurohigher proportion of • Relatively surgical facilities craniopharyngioma [41] of co-ordinated multi-disciplinary care (only • Lack 56 % received appropriate therapy post surgery age of presentation • Later (29–34months) [44,45,46] proportion of extra-ocular • More disease (up to 40 % cases) [47] higher proportion of • Relative advanced/metastatic disease at presentation especially for neuroblastoma. [53]
•
[43])
of 63–92 % (compared to upto 95% abandonment is more than 50 % and • OS • Treatment in HICs) seen especially before key intervention of 3 yr OS 47-61% (80% • Neuroblastoma: in HICs) [53,54,57] tumour: 70-85% survival (92% • Wilms’ in HICs) [55,56,57,58] 5 yr OS 50% (69% in • Osteosarcoma: HICs) [57,64] sarcoma: 5 yr OS 52.4% • Ewing’s (localized) and 16.4% (metastatic)
•
• • •
(76% in HICs) [57,70,71] Rhabdomyosarcoma: Data scarce. 5 yr EFS between 43-57% (compared to OS of 70% in HICs) [57,72,73]
enucleation or leading to inadequate chemoprophylaxis [23]. More advanced stage of presentation precludes upfront surgery in Wilms’ tumour or neuroblastoma. Treatment abandonment remains common before interventions like amputations in bone tumours or soft tissue sarcomas [23] Lack of multi-disciplinary care leading to suboptimal and incomplete treatment in many cases
*ALL = Acute Lymphoblastic Leukaemia, AML = Acute Myeloid Leukaemia, OS = Overall Survival, EFS = Event Free Survival, HIC=High income countries, CNS = Central Nervous System.
properly instituted due to significant refusal and abandonment.
in various studies and besides financial constraints, unwillingness for enucleation, a key therapeutic intervention, may be a major cause for the same [44,47–49]. However, it is encouraging to note that rate of treatment refusal is coming down over years and it has also been shown that proper pre-treatment counselling and effective tracking mechanism can prevent treatment abandonment in retinoblastoma [44,49]. Resource constraints limit easy availability of imaging modalities like MRI which causes difficulty during staging evaluation [50]. Increasing awareness and incorporation of red reflex testing during routine visit to primary care physician or paediatrician may pick up early cases and prevent delayed presentation in retinoblastoma [50].
3.4. Retinoblastoma Incidence rate of retinoblastoma in India is 4.3 pm which is similar to other HICs however, it contributes to 6–10% of all childhood cancer cases in India [7,12]. This higher relative proportion is likely due to ready recognition and diagnosis of retinoblastoma with comparatively missed diagnoses of other group of malignancies. The mean age of presentation varies between 29–34 months in various institutional reviews which is significantly late as compared to HICs [44,45]. Leukocoria remains the most common presentation followed by strabismus, proptosis, visual loss and red eye [44–46]. Poor socio-economic status and lack of awareness leads to missed leukocoria by parents and they generally seek care in more advanced stage with obvious proptosis or visual loss. While extraocular disease at presentation was observed in 9 % cases in a tertiary care centre in South India, similar studies showed extraocular disease in 27–40 % cases in North India with metastatic disease in 10 % cases [44,46–48]. This is likely responsible for widely varying survival outcome ranging from 92 % in the centre from South India to 63 % in North India [44,46]. Treatment denial and abandonment proportion was more than 50 %
3.5. Other solid malignancies 3.5.1. Neuroblastoma Neuroblastoma accounts for 4.2–8.3 % of paediatric cancer incidence in India [38]. The earlier population-based studies based on cancer registry data showed 5-year OS of 28 % and 36.9 % from South India [13,51]. A review revealed survival outcome ranging from 8.7 to 80% [52]. A single centre experience of 144 children in North India revealed more than 80 % presenting in advanced stages (INSS stage 3/ 4) with predominant intra-abdominal disease; 3-year OS was 60.7 % although, it was 35.7 % in stage 4 disease [53]. Similar finding was 5
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reported from South India with 3-year OS and EFS of 47 % and 36 % respectively [54].
clinical trials [76,77]. 4.3. Financial support and holistic care
3.5.2. Wilms’ tumour The reported survival rate, ranging from 70 to 85%, is slightly inferior to Western data, which may be due to late presentation and advanced stage at presentation [55–58]. Due to rarity of tumour and subsequent lack of expertise, often upfront surgery with suboptimal surgical staging is a common phenomenon. In such a scenario, a 3-drug chemotherapy regimen including anthracycline may be routinely employed for improvement of outcome [59]. In other cases, it is more prudent to follow neoadjuvant chemotherapy followed by surgery in view of more advanced presentation [60].
Philanthropic support, which provided holistic care including support for nutrition, accommodation and transfusion, translated into significant drop in treatment abandonment and improved outcome in a tertiary care centre, and their role deserves special mention [78,79]. Since, the cost of cancer care is often financially prohibitive due to significant out of pocket expenditure, the introduction of the National Health Protection Scheme under Ayushman Bharat Program by Government of India is likely to ensure healthcare access for financially needy. This program, “the world’s largest government sponsored healthcare insurance scheme”, aims to provide coverage up to 500,000 Indian Rupees per family per year covering nearly 40 % of the population targeted towards economically and socially vulnerable population defined by nationally conducted surveys [80–82]. The availability of anti-neoplastic drugs for childhood cancer is still low in both public and private healthcare pharmacies and also remains unaffordable; streamlining medicine procurement and promotion of health insurance is being done by the government to address the same [83,84].
3.5.3. Bone and soft tissue tumours Malignant bone tumours account for 10–12 % of total childhood cancer burden in India [38]. While high dose methotrexate-based combination regimens are commonly used in resource-rich settings for osteosarcoma, logistic issues regarding administration and management of toxicities precludes its use in Indian scenario [61–63]. A single centre analysis of 237 patients of non-metastatic osteosarcoma with nonmethotrexate based regimen showed 5-year OS of 50.3 % while another study from South India showed 3-year OS of 54.6 % [64,65]. Capacity building of orthopaedic oncology and easy availability of techniques like extra-corporeal radiotherapy with improved joint preservation will further help in improving outcome in osteosarcoma [66]. While Ewing’s sarcoma is readily recognizable when presenting in extremities, it may be difficult to recognize in uncommon sites like spine and may lead to misdiagnosis of tuberculosis of spine in Indian setting [67]. Earlier studies in India showed 3-year DFS of 55 % in localized disease and 5-year DFS of 38 % in another mixed cohort [68,69]. A large institutional review from North India in localized Ewing sarcoma showed 5-year OS 52.4 % [70]; the study also revealed spine or abdomino-pelvic location, higher TLC and in case of extremity site, longer symptom duration and larger tumour size to be associated with inferior EFS. In metastatic setting, which was seen in around 40 % of patients, 5-year OS was 16.9 % with hypoalbuminemia as a poor prognostic factor [71]. In rhabdomyosarcoma, data on outcome is scarce with two retrospective institutional analysis showing 5-year EFS of 43.6 % and 57.1 %, and treatment refusal and abandonment were reported as a major hurdle in management [72,73].
4.4. The way forward 4.4.1. Addressing toxicity and treatment abandonment While a more intensive protocol may result in decreasing relapse rate but the increased incidence of toxicity, which is more common in presence of malnutrition and absence of proper support structure, may offset survival advantage [85]. Hence, a pragmatic balance is necessary in adopting uniform treatment protocols along with strengthening of supportive care logistics. It is also important to focus on proper pretreatment counselling allaying anxiety and undue fear regarding diagnosis of cancer so that drop-outs are reduced, and effective telephonic tracking mechanism to ensure that each child receives complete care. 4.4.2. Improving data collection The low coverage, conventional method of data acquisition with high cost, low quality assurance of data remains significant challenges in the functioning PBCRs [5]. Setting up of new PBCRs to increase coverage, linking PBCRs with HBCRs as well as improvement of method of data collection by harnessing technological advances will help in capturing the real incidence and burden of childhood cancer.
4. Progress in last few decades and the way forward
4.4.3. Early recognition and referral Childhood cancer is predominantly not amenable to preventive strategies. Rather early recognition, prompt diagnosis and referral is the key to improvement of survival outcome. Self-reported confidence of undergraduate students in suspecting and referring childhood cancer cases is lacking even after their paediatric clinical training which suggests need for more focus on childhood cancer in training curriculums [86]. The regular training of paediatricians through National Training Project in Practical Paediatric Oncology under IAP PHO Chapter is an important initiative which will promote early recognition and referral of childhood cancer cases [87]. The development of training program for paediatric oncology nursing as well as other paramedical disciplines is additionally required for dissemination of paediatric oncology services.
4.1. Establishment of training programs Paediatric oncology services in India were at a nascent stage in 1980s and predominantly restricted to first tier urban centres. The establishment of formal training programs in paediatric oncology in the form of fellowships and subspecialty degree courses within the last decade will help in capacity building and decentralization of paediatric oncology services from first tier cities to second and third tier cities [74]. 4.2. Standardization of treatment protocols and multi-centre collaborations Adoption of uniform MCP-841 protocol have resulted in improved survival in ALL [17]. The initiation of a collaborative, multi-centre, national trial for newly diagnosed patients with ALL called Indian Childhood Collaborative Leukaemia group (ICiCLe) Protocol in 2014 exemplifies the ongoing efforts of collaborative research in India [75]. The establishment of Paediatric Haematology and Oncology (PHO) Chapter under Indian Academy of Paediatrics (IAP) in 1987 followed by development of Indian Paediatric Oncology Group (InPOG) in 2008 has further developed the roadmap for conducting prospective multi-centre
4.4.4. Improving gender bias The multiple initiatives taken by Government of India for sensitization and education of general population against gender-based discrimination, including flagship program like “Beti Bachao Beti Padhao” (Save and Educate Daughters), will also help to address gender bias in seeking healthcare for girl child and will go a long way in improving overall cancer care in the country [88,89]. In conclusion, the outcome of childhood cancer in India has shown 6
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significant improvement in past decades with development of multidisciplinary care, collaborative trials and adoption of treatment protocols with holistic support from various organizations.
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Cancer Epidemiology journal homepage: www.elsevier.com/locate/canep
Childhood cancer in India Shuvadeep Gangulya, Sally Kinseyb, Sameer Bakhshia,* a b
Department of Medical Oncology, IRCH, AIIMS, New Delhi, India Department of Paediatric Haematology, University of Leeds, Honorary Consultant Paediatric Haematologist, Leeds Teaching Hospitals Trust, Leeds, UK
ARTICLE INFO
ABSTRACT
Keywords: Child Cancer India Survival Incidence Epidemiology Mortality Health services
India has made significant improvement in childhood cancer services in last few decades. However, the outcome still remains modest as compared to global standards due to significant barriers in recognition, diagnosis and cure. Data regarding comprehensive childhood cancer burden in country is lacking due to low and urban predominant coverage of population-based cancer registry programs. The available data shows lower incidence of childhood cancer incidence especially in leukaemia and CNS tumours which may suggest poor awareness of caregivers and delayed diagnosis with many “missed cases”. Incidence data are also skewed towards male preponderance which suggests gender bias in seeking healthcare. The childhood cancer services in India are predominantly restricted to few tertiary care centres in major cities. The outcome in major groups of cancer is complicated by delayed and more advanced stage of presentation and poor supportive care during intensive treatment. Treatment refusal and abandonment remains major hurdles. Last few decades saw development of dedicated paediatric oncology services and training programs in the country. The development of InPOG (Indian Paediatric Oncology group) for conducting collaborative trials will lead to adoption of uniform treatment protocols suited for the country. Financial support through the government promoted health insurance and holistic support through philanthropic organizations have improved treatment adherence and outcome. Moving forward, the focus should be on strengthening the cancer registries for capturing nationwide data, improving awareness of childhood cancer among caregivers and healthcare workers for early recognition and improving accessibility of childhood cancer care services beyond major cities.
1. Background Currently, more than 80 % of children diagnosed with cancer will become long-term survivors in high income countries (HICs) [1]. Low and middle-income countries (LMICs), including India, account for nearly 90 % of paediatric population and more than 80 % of childhood cancer burden [2,3]. Inequality in healthcare access, lack of adequately trained manpower, treatment abandonment and myriad of other factors have led to only modest improvement in childhood cancer outcome in LMICs in contrast to HICs [4]. In India, although great progress has been made in last few decades, a lot of barriers exist in the pathway from diagnosis to cure. There is lack of high-quality data which captures nation-wide incidence, survival and morbidity of childhood cancer [5]. The focus of healthcare policy of the country is towards more pressing issues like reproductive
health, communicable diseases, malnutrition with less focus towards childhood cancer which forms significantly small proportion of total cancer cases. In this review, we compare incidence and outcome of childhood cancer in India with global standards, attempt to elucidate various barriers in pathway from diagnosis to cure in different healthcare settings of the country, summarize the progress made so far and the way forward. 2. Childhood cancer burden in India: comparison with global standards The data on childhood cancer burden in India predominantly stems from population-based cancer registries (PBCRs) and hospital-based cancer registries (HBCRs) along with disease-specific institutional
⁎ Corresponding author at: Department of Medical Oncology Dr. BRA Institute Rotary Cancer Hospital All India Institute of Medical Sciences, New Delhi, 110029, India. E-mail address: [email protected] (S. Bakhshi).
https://doi.org/10.1016/j.canep.2020.101679 Received 18 October 2019; Received in revised form 8 January 2020; Accepted 9 January 2020 1877-7821/ © 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Shuvadeep Ganguly, Sally Kinsey and Sameer Bakhshi, Cancer Epidemiology, https://doi.org/10.1016/j.canep.2020.101679
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Fig. 1. Location of population-based cancer registries and hospital based cancer registries in India (*Map of India adapted from outline map of India from Survey of India, Department of Science and Technology, Govt of India).
of Million Death study estimated childhood cancer mortality at 37/ million/year; this is significantly higher than previous estimates with large disparity noted in CNS tumours; notably, only around 4–5 % of children received any form of cancer-directed therapy before death, even though 82.5 % presented to hospital facilities before death. This highlights significant barriers that exist in accessing cancer healthcare services for children [11].
reviews. Currently, with 33 PBCRs and 29 HBCRs functioning in India including regional cancer centres (Fig. 1) and with new centres being constantly added to the network, population coverage still remains low at only 10 % with significant urban dominance [5,6]. Cancer incidence patterns are related with socio-economic development with HICs reporting higher incidence compared to LMICs [4,7]. Childhood cancer in India accounts for 0.7-4.4 % of total cancer diagnoses as per PBCR report (2012-14) which is nearly similar to previous PBCR report of 0.5-5.8 % (2009-11) [8,9]. Age-adjusted incidence rate per million (AARpm) showed a wide variation with Delhi having highest AARpm for all types of childhood cancers in both boys and girls at 235.3and 152.3 respectively followed by PBCR Chennai in South India (156.7 for boys and 85.6 for girls) and Aizawl district in north-eastern India (136.1 for boys and 88.7 for girls) [8]. This unusual high incidence of childhood cancer in Delhi is likely due to referral bias in view of the location of major hospitals with paediatric oncology services in the capital although, the role of exposure to other risk factors needs to be investigated. As per the report of International Incidence of childhood cancer volume-3, age-standardized rate of childhood cancer incidence in India from records of 7 registries is 96.9 pm which is significantly lower than countries like US (166.9 pm), Canada (164.9 pm), UK (140.5 pm) or Australia (154.9 pm) (Fig. 2A and B) [7]. It is worthwhile to note the gender variation in childhood cancer incidence in India where male to female ratio is 1.56 while it is between 1.12–1.15 in HICs, which may suggest gender bias in seeking care (Fig. 3). Gender-based discrimination against girl child is a phenomenon seen in Southeast Asian countries which translates into delayed healthcare seeking for all childhood illnesses including cancer [10]. The incidence of central nervous system (CNS) tumours and leukaemia is significantly lower than in HICs (Fig. 2A and B), which perhaps signify that a large proportion of cases remain undiagnosed. A nationally representative study which used verbal autopsy reports
3. Pathway to cure and its barriers The epidemiology and outcome of respective childhood cancers in Indian context is summarized along with discussion about existing gaps and limitations specific to each group along with suggestions to improve the existing barriers (Tables 1 and 2) 3.1. Leukaemia Leukaemia accounts for 40–50 % of childhood cancer burden in India with acute lymphoblastic leukaemia (ALL) being the commonest type [7,12]. There is a paucity of population-based studies showing outcome of paediatric ALL in India, however, one study showed 5-year overall survival (OS) of 38.7 % (1990–2001) [13]. A recent review summarizing the outcome of ALL in various hospital-based studies, showed OS between 45–81 % and event free survival (EFS) between 41–70 % although, outcome in patients who defaulted was unknown [14–19]. The median age of presentation in various studies is between 6–10 years which is comparatively later than in HICs [14,20]. The initial multi-centric study, which attempted to elucidate risk factors for paediatric ALL in India, showed increased WBC count and more extensive disease (in form of lymphadenopathy and hepatosplenomegaly) at presentation, more frequency of T-cell immunophenotype (21.1–42.7 %) with lower percentage of TEL-AML1 and higher percentage of BCR2
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Fig. 2. A: Age standardized incidence rates of major groups of childhood cancer (0–14years) in India and comparison with selected population (Data compiled from International Incidence of Childhood cancer volume III [7]). B: Relative proportion of major group of childhood cancer in India and other selected countries (Data compiled from International Incidence of Childhood cancer volume III [7]).
ABL positive cases [17,21]. Similar findings have been reported in other studies though, it is prudent to observe that cytogenetic and molecular analysis could not be routinely done in most centres due to paucity of resource, availability and expertise [16,19,22]. This late median age of presentation and high-risk disease phenotype may suggest a high-risk disease biology in Indian ethnicity. However, it may also be due to the fact that more florid presentation with high risk disease biology may be easily recognized and referred while more insidious onset TEL-AML1 transcript positive pre-B ALL cases are likely missed or recognized significantly late. A study from North India showed initial treatment refusal rate of 30.2 % and subsequent rate of treatment default of around 14.5 % [18]. Treatment default significantly occurred during induction and is multifactorial [23,24]. In paediatric AML, a recent review reported 6–45 % toxicity-related deaths in various studies and relapse rates between 26–48 % [14]. Five-
year OS from an institutional series from North India was 35.5 % with induction mortality of 18 % [25]. A significant proportion of patients have extramedullary presentation which is associated with better outcome [26]. The treatment refusal rate ranged from 6 to 20% in tertiary care centres in India and financial support necessary for majority of families for affording care in first tier cities was possible only in major government-funded hospitals [27]. 3.2. Lymphoma The overall incidence of childhood lymphoma in India is similar to that of Western population; the relative proportion of Hodgkin lymphoma (HL) was higher in earlier epidemiological review although this finding was not reflected in latest PBCR report [7,8,12].
Fig. 3. Age standardized incidence rate per million of childhood cancer of boys and girls in India and other selected countries (Data compiled from International Incidence of Childhood cancer volume III [7]). 3
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Table 1 General barriers in the pathway to childhood cancer diagnosis and cure in India with suggestions for improvement. Barriers 1 Barriers to diagnosis a Late presentation to the healthcare facility
a Delayed diagnosis
Probable underlying factors
Suggestions for addressing the barrier
of awareness among caregivers regarding early signs (like • Lack leukocoria in retinoblastoma) for traditional or alternative medications • Preference of healthcare facilities nearby • Inaccessibility and socio-economic status • Education • Gender bias in seeking healthcare for girl child of expertise in grassroots healthcare workers in recognizing • Lack signs of childhood cancer (missed cases of CNS tumours, misdiagnosis of tuberculosis)
of diagnostic facilities in peripheral centres with lack of • Lack expertise for interpretation (especially MRI facilities, 2 Barriers to cure a Treatment denial and abandonment [79]
a Treatment toxicity a Suboptimal care
immunophenotyping)
belief and irrational fear about cancer curability • Personal difficulties and logistics • Financial with care received • Dissatisfaction for key interventions which are aggressive (enucleation/ • Refusal amputation) or have multiple painful procedures (bone marrow/ intrathecal drug administration)
support structure, lack of transfusion support • Poor • Malnutrition incidence of sepsis • High is localized in few centres • Expertise of co-ordination between specialists for constitution of • Lack tumour boards. availability of anti-neoplastic drugs [80] • Less surgery or treatment at peripheral healthcare centre • Suboptimal (especially Wilms tumour and neuroblastoma) or by alternative
of parents and general population about common • Education childhood cancers and its high curability. of healthcare delivery facilities at peripheral level • Improvement through community wellness centres as envisioned under Ayushman Bharat program.
of population towards gender bias through • Sensitization government flagship programs. of healthcare workers and general practitioners/ • Training paediatricians for recognising early signs of childhood cancer. of paediatric oncology services through district level • Strengthening healthcare facilities.
counselling to allay anxiety of caregivers and to • Pre-treatment inform about high curability of childhood cancers and need for complete treatment to achieve good outcome.
tracking mechanisms and telephonic follow up for • Effective minimizing dropouts of holistic support structure for transfusion • Development support, nutrition through collaborations, accommodation
support for financially needy patients from faraway places.
programs for paediatric oncology as well as allied • Training services to disseminate expertise. decision making through multi-disciplinary tumour • Increasing boards to ensure proper and complete treatment delivery
medicine practitioners
*CNS = Central Nervous System, MRI = Magnetic resonance imaging.
3.2.1. Hodgkin lymphoma HL in India is characterized by younger age of presentation and predominance of mixed cellularity histopathology which may be due to subclinical Epstein Barr Virus infection in childhood [12,28]. In various institutional reviews, between 40–60 % of children presented with advanced stage disease with more proportion of patients reporting B symptoms [28,29]. Indolent nature of presentation and frequent misdiagnosis of tuberculosis, especially in a high tuberculosis prevalence area like India, contributes to delayed presentation and similar findings have been observed in other settings as well [30]. In an institutional series, 46 % of patients received empirical anti-tubercular therapy before diagnosing HL which suggests need for generating awareness for early suspicion and referral [28]. Five-year OS in paediatric HL is above 90 % with EFS between 83–87 % which is almost similar albeit slightly lower than HICs [1,28,29]. In early stage HL, the survival outcome is excellent with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) regimen with 10-year OS of 98.9 % [31]. Even in advanced cases, ABVD has reasonable outcome with 5-year OS of 95.3 % and freedom from treatment failure of 84.8 % [32]. This encouraging finding suggests that survival outcome of paediatric HL in India nearly parallels global standards which may be likely due to simpler treatment protocols and intrinsic chemosensitivity of the disease, although delayed presentation remains a major barrier.
EFS of 72 %, 55.8 % and 27.5 % in BL, ALCL and DLBCL respectively, while outcome with uniform BFM-90 protocol in advanced paediatric BNHL from North India showed 5-year OS of 61 % and EFS of 52 %, which is inferior to HICs [34,36]. In early-stage non-blastic NHL, short course reduced intensity protocol achieved reasonably good outcome with possible reduced toxicities [37]. The data regarding accessibility of multi-disciplinary care, treatment abandonment or denial in paediatric NHL is lacking which precludes extrapolation of these findings on overall Indian population. 3.3. CNS tumours CNS tumours account for 8–12 % of total childhood cancer cases as per consolidated HBCR (2012-14) report [38]. In a multi-institutional review, astrocytoma and medulloblastoma remains the two most common paediatric brain malignancy followed by primitive neuro-ectodermal tumour, craniopharyngioma and ependymal tumours [39]. The relative proportion of tumours is similar to Western data with a relatively higher incidence of craniopharyngioma in India [39–41]. The relatively lower incidence of paediatric CNS tumours in India may be likely due to poor recognition and missed diagnosis as the common presenting symptoms are headache, vomiting and seizures, which can often be non-specific in younger children [42]. Hence, in absence of readily available neuro-imaging and neurosurgical facilities which is limited to predominantly tertiary care institutions, a large proportion of cases may be misdiagnosed and treated as meningo-encephalitis [12]. A retrospective institutional review showed 15.3 % mortality on follow-up however, another 44 % abandoned treatment and subsequent outcome was not reported; only 56 % could receive complete treatment as per protocol [43]. Another study also reported 32 % refusal rate for radiotherapy after surgery.(14) The above findings suggest that multimodality treatment even though available in select centres could not be
3.2.2. Non-Hodgkin lymphoma (NHL) In institutional reviews, the most common presenting feature is abdominal symptoms followed by constitutional symptoms and lymphadenopathy with a significant proportion of cases presenting in advanced stages [33–35]. Burkitt’s lymphoma (BL) (40–60 %) and lymphoblastic lymphoma (30–40 %) remains the predominant subtypes followed by anaplastic large cell lymphoma (ALCL) and diffuse large Bcell lymphoma (DLBCL). Experience from South India showed 2-year 4
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Table 2 Differences in presentation and outcome of specific groups of childhood cancer in India with disease specific barriers to management: Group of childhood cancer Leukaemia ALL
•
• AML
Lymphoma Hodgkin lymphoma(HL)
•
• Non Hodgkin lymphoma CNS Tumours
Retinoblastoma
Other solid tumours Neuroblastoma Wilms’ tumour Bone tumours Osteosarcoma Ewing’s sarcoma Rhabdomyosarcoma
• • •
Presentation in India as compared to HICs
Outcome in India as compared to HICs
Specific barriers in management
age of presentation (6–10 years) 45–81 % compared to nearly 90% recognition of insidious onset pre-B ALL • Later • OS • Delayed [14,20] in HICs. [14,57] (anaemia and fever are often missed or treated for nutritional anaemia) T-cell immunophenotype • More high-risk cytogenetics/molecular Lack of easy availability of immunophenotyping • More • features [17,21] and expertise in peripheral centres leading to delayed diagnosis and repeated bone marrow proportion with Data is scarce with 5-year OS of 30–35 • Significant • extramedullary presentation (up to % (compared to 68% in HICs) examinations. 21.2 %) [26] [25,26,57] abandonment especially in induction • Treatment phase with multiple painful procedures (Intrathecal
age of presentation (8-10years) OS around 90 % (compared to • Earlier • 5-98 year • [28] % in HICs) [28,29,57] proportion of mixed cellularity • More histopathology [28] • children with advanced stage stage and 90 • More • 5%yrinOSearly61 %stagein advanced /with B symptoms [34,35] (compared to more than 80 % in HICs) [36,37,57]
drug administration/ bone marrow) or due to toxicity (experienced in up to 45 % of patients during AML induction [14]) Delayed recognition due to misdiagnosis of tuberculosis (seen in up to 46 % of diagnosed cases of HL). [30] Common use of steroids in peripheral healthcare facility without diagnosis complicates the diagnosis of leukaemia or lymphoma further down the line.
of CNS tumours is nearly 50 data. 15.3 % mortality in recognition or missed diagnosis due to • Incidence • Scarce • Delayed % of that in HICs. [7] institutional follow up (with significant non-specific symptoms in younger children and treatment drop out) [43] lack of easily available neuro-imaging and neurohigher proportion of • Relatively surgical facilities craniopharyngioma [41] of co-ordinated multi-disciplinary care (only • Lack 56 % received appropriate therapy post surgery age of presentation • Later (29–34months) [44,45,46] proportion of extra-ocular • More disease (up to 40 % cases) [47] higher proportion of • Relative advanced/metastatic disease at presentation especially for neuroblastoma. [53]
•
[43])
of 63–92 % (compared to upto 95% abandonment is more than 50 % and • OS • Treatment in HICs) seen especially before key intervention of 3 yr OS 47-61% (80% • Neuroblastoma: in HICs) [53,54,57] tumour: 70-85% survival (92% • Wilms’ in HICs) [55,56,57,58] 5 yr OS 50% (69% in • Osteosarcoma: HICs) [57,64] sarcoma: 5 yr OS 52.4% • Ewing’s (localized) and 16.4% (metastatic)
•
• • •
(76% in HICs) [57,70,71] Rhabdomyosarcoma: Data scarce. 5 yr EFS between 43-57% (compared to OS of 70% in HICs) [57,72,73]
enucleation or leading to inadequate chemoprophylaxis [23]. More advanced stage of presentation precludes upfront surgery in Wilms’ tumour or neuroblastoma. Treatment abandonment remains common before interventions like amputations in bone tumours or soft tissue sarcomas [23] Lack of multi-disciplinary care leading to suboptimal and incomplete treatment in many cases
*ALL = Acute Lymphoblastic Leukaemia, AML = Acute Myeloid Leukaemia, OS = Overall Survival, EFS = Event Free Survival, HIC=High income countries, CNS = Central Nervous System.
properly instituted due to significant refusal and abandonment.
in various studies and besides financial constraints, unwillingness for enucleation, a key therapeutic intervention, may be a major cause for the same [44,47–49]. However, it is encouraging to note that rate of treatment refusal is coming down over years and it has also been shown that proper pre-treatment counselling and effective tracking mechanism can prevent treatment abandonment in retinoblastoma [44,49]. Resource constraints limit easy availability of imaging modalities like MRI which causes difficulty during staging evaluation [50]. Increasing awareness and incorporation of red reflex testing during routine visit to primary care physician or paediatrician may pick up early cases and prevent delayed presentation in retinoblastoma [50].
3.4. Retinoblastoma Incidence rate of retinoblastoma in India is 4.3 pm which is similar to other HICs however, it contributes to 6–10% of all childhood cancer cases in India [7,12]. This higher relative proportion is likely due to ready recognition and diagnosis of retinoblastoma with comparatively missed diagnoses of other group of malignancies. The mean age of presentation varies between 29–34 months in various institutional reviews which is significantly late as compared to HICs [44,45]. Leukocoria remains the most common presentation followed by strabismus, proptosis, visual loss and red eye [44–46]. Poor socio-economic status and lack of awareness leads to missed leukocoria by parents and they generally seek care in more advanced stage with obvious proptosis or visual loss. While extraocular disease at presentation was observed in 9 % cases in a tertiary care centre in South India, similar studies showed extraocular disease in 27–40 % cases in North India with metastatic disease in 10 % cases [44,46–48]. This is likely responsible for widely varying survival outcome ranging from 92 % in the centre from South India to 63 % in North India [44,46]. Treatment denial and abandonment proportion was more than 50 %
3.5. Other solid malignancies 3.5.1. Neuroblastoma Neuroblastoma accounts for 4.2–8.3 % of paediatric cancer incidence in India [38]. The earlier population-based studies based on cancer registry data showed 5-year OS of 28 % and 36.9 % from South India [13,51]. A review revealed survival outcome ranging from 8.7 to 80% [52]. A single centre experience of 144 children in North India revealed more than 80 % presenting in advanced stages (INSS stage 3/ 4) with predominant intra-abdominal disease; 3-year OS was 60.7 % although, it was 35.7 % in stage 4 disease [53]. Similar finding was 5
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reported from South India with 3-year OS and EFS of 47 % and 36 % respectively [54].
clinical trials [76,77]. 4.3. Financial support and holistic care
3.5.2. Wilms’ tumour The reported survival rate, ranging from 70 to 85%, is slightly inferior to Western data, which may be due to late presentation and advanced stage at presentation [55–58]. Due to rarity of tumour and subsequent lack of expertise, often upfront surgery with suboptimal surgical staging is a common phenomenon. In such a scenario, a 3-drug chemotherapy regimen including anthracycline may be routinely employed for improvement of outcome [59]. In other cases, it is more prudent to follow neoadjuvant chemotherapy followed by surgery in view of more advanced presentation [60].
Philanthropic support, which provided holistic care including support for nutrition, accommodation and transfusion, translated into significant drop in treatment abandonment and improved outcome in a tertiary care centre, and their role deserves special mention [78,79]. Since, the cost of cancer care is often financially prohibitive due to significant out of pocket expenditure, the introduction of the National Health Protection Scheme under Ayushman Bharat Program by Government of India is likely to ensure healthcare access for financially needy. This program, “the world’s largest government sponsored healthcare insurance scheme”, aims to provide coverage up to 500,000 Indian Rupees per family per year covering nearly 40 % of the population targeted towards economically and socially vulnerable population defined by nationally conducted surveys [80–82]. The availability of anti-neoplastic drugs for childhood cancer is still low in both public and private healthcare pharmacies and also remains unaffordable; streamlining medicine procurement and promotion of health insurance is being done by the government to address the same [83,84].
3.5.3. Bone and soft tissue tumours Malignant bone tumours account for 10–12 % of total childhood cancer burden in India [38]. While high dose methotrexate-based combination regimens are commonly used in resource-rich settings for osteosarcoma, logistic issues regarding administration and management of toxicities precludes its use in Indian scenario [61–63]. A single centre analysis of 237 patients of non-metastatic osteosarcoma with nonmethotrexate based regimen showed 5-year OS of 50.3 % while another study from South India showed 3-year OS of 54.6 % [64,65]. Capacity building of orthopaedic oncology and easy availability of techniques like extra-corporeal radiotherapy with improved joint preservation will further help in improving outcome in osteosarcoma [66]. While Ewing’s sarcoma is readily recognizable when presenting in extremities, it may be difficult to recognize in uncommon sites like spine and may lead to misdiagnosis of tuberculosis of spine in Indian setting [67]. Earlier studies in India showed 3-year DFS of 55 % in localized disease and 5-year DFS of 38 % in another mixed cohort [68,69]. A large institutional review from North India in localized Ewing sarcoma showed 5-year OS 52.4 % [70]; the study also revealed spine or abdomino-pelvic location, higher TLC and in case of extremity site, longer symptom duration and larger tumour size to be associated with inferior EFS. In metastatic setting, which was seen in around 40 % of patients, 5-year OS was 16.9 % with hypoalbuminemia as a poor prognostic factor [71]. In rhabdomyosarcoma, data on outcome is scarce with two retrospective institutional analysis showing 5-year EFS of 43.6 % and 57.1 %, and treatment refusal and abandonment were reported as a major hurdle in management [72,73].
4.4. The way forward 4.4.1. Addressing toxicity and treatment abandonment While a more intensive protocol may result in decreasing relapse rate but the increased incidence of toxicity, which is more common in presence of malnutrition and absence of proper support structure, may offset survival advantage [85]. Hence, a pragmatic balance is necessary in adopting uniform treatment protocols along with strengthening of supportive care logistics. It is also important to focus on proper pretreatment counselling allaying anxiety and undue fear regarding diagnosis of cancer so that drop-outs are reduced, and effective telephonic tracking mechanism to ensure that each child receives complete care. 4.4.2. Improving data collection The low coverage, conventional method of data acquisition with high cost, low quality assurance of data remains significant challenges in the functioning PBCRs [5]. Setting up of new PBCRs to increase coverage, linking PBCRs with HBCRs as well as improvement of method of data collection by harnessing technological advances will help in capturing the real incidence and burden of childhood cancer.
4. Progress in last few decades and the way forward
4.4.3. Early recognition and referral Childhood cancer is predominantly not amenable to preventive strategies. Rather early recognition, prompt diagnosis and referral is the key to improvement of survival outcome. Self-reported confidence of undergraduate students in suspecting and referring childhood cancer cases is lacking even after their paediatric clinical training which suggests need for more focus on childhood cancer in training curriculums [86]. The regular training of paediatricians through National Training Project in Practical Paediatric Oncology under IAP PHO Chapter is an important initiative which will promote early recognition and referral of childhood cancer cases [87]. The development of training program for paediatric oncology nursing as well as other paramedical disciplines is additionally required for dissemination of paediatric oncology services.
4.1. Establishment of training programs Paediatric oncology services in India were at a nascent stage in 1980s and predominantly restricted to first tier urban centres. The establishment of formal training programs in paediatric oncology in the form of fellowships and subspecialty degree courses within the last decade will help in capacity building and decentralization of paediatric oncology services from first tier cities to second and third tier cities [74]. 4.2. Standardization of treatment protocols and multi-centre collaborations Adoption of uniform MCP-841 protocol have resulted in improved survival in ALL [17]. The initiation of a collaborative, multi-centre, national trial for newly diagnosed patients with ALL called Indian Childhood Collaborative Leukaemia group (ICiCLe) Protocol in 2014 exemplifies the ongoing efforts of collaborative research in India [75]. The establishment of Paediatric Haematology and Oncology (PHO) Chapter under Indian Academy of Paediatrics (IAP) in 1987 followed by development of Indian Paediatric Oncology Group (InPOG) in 2008 has further developed the roadmap for conducting prospective multi-centre
4.4.4. Improving gender bias The multiple initiatives taken by Government of India for sensitization and education of general population against gender-based discrimination, including flagship program like “Beti Bachao Beti Padhao” (Save and Educate Daughters), will also help to address gender bias in seeking healthcare for girl child and will go a long way in improving overall cancer care in the country [88,89]. In conclusion, the outcome of childhood cancer in India has shown 6
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significant improvement in past decades with development of multidisciplinary care, collaborative trials and adoption of treatment protocols with holistic support from various organizations.
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